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Active drug substance impurity profiling part II. LC/MS/MS fingerprinting

E C Nicolas1, T H Scholz

  • 1The DuPont Merck Pharmaceutical Company, Deepwater, NJ 08023, USA.

Journal of Pharmaceutical and Biomedical Analysis
|April 16, 1998
PubMed
Summary

Liquid chromatography-mass spectrometry/mass spectrometry (LC/MS/MS) generates reproducible impurity fingerprints for drug substances. This method aids in identifying new impurities and characterizing existing ones, even positional isomers, without standards.

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Area of Science:

  • Analytical Chemistry
  • Pharmaceutical Analysis
  • Mass Spectrometry

Background:

  • High-Performance Liquid Chromatography (HPLC) is standard for monitoring drug substance impurities.
  • Variable retention times in HPLC can cause ambiguity in impurity identification.
  • Characterizing impurities online is crucial when impurity standards are unavailable.

Purpose of the Study:

  • To evaluate Liquid Chromatography-Mass Spectrometry/Mass Spectrometry (LC/MS/MS) for generating characteristic impurity fingerprints.
  • To assess the reproducibility of these fingerprints across different batches of a drug substance.
  • To explore the utility of MS/MS fingerprinting for distinguishing isomers and assigning tentative structures.

Main Methods:

  • Generated MS/MS fingerprints (precursor ion mass + ≥3 product ion masses) for a drug substance (DuP 941) and its impurities using standards.

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  • Optimized collision cell parameters, identifying collision energy as critical for reproducible fingerprint generation.
  • Performed online MS/MS fingerprinting for seven impurities in an early drug substance lot and compared them to subsequent lots.

    • Main Results:

    • Reproducible MS/MS impurity fingerprints were generated, with high consistency observed across different drug substance lots, even for impurities at 0.01 UV area percent.
    • MS/MS fingerprinting successfully differentiated between two known positional isomers.
    • The method facilitated the tentative structural assignment of drug impurities.

    Conclusions:

    • LC/MS/MS provides a robust method for generating reproducible impurity fingerprints in drug substances.
    • This technique is valuable for online impurity characterization, isomer differentiation, and structural elucidation, especially when standards are lacking.
    • MS/MS fingerprinting enhances the reliability of impurity monitoring in pharmaceutical development and quality control.